Inhibition of Ligand-Gated TRPA1 by General Anesthetics
Inhibition of Ligand-Gated TRPA1 by General Anesthetics
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DOI：
10.1124/mol.119.118851
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发表时间：
2020-09-01
影响因子：
3.6
通讯作者：
Ahern, Gerard P.
中科院分区：
文献类型：
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作者：
Hoai T Ton;Thieu X Phan;Ahern, Gerard P.
几种全身麻醉药（GA）在给药后产生疼痛或刺激，这主要通过激活伤害性离子通道，瞬时受体电位锚蛋白1型（TRPA 1）发生。然而，GAs对激动剂介导的TRPA 1活性的影响尚不清楚。在这里，我们表明，不同范围的有毒和无毒挥发性麻醉剂，在临床相关浓度，抑制配体激活的TRPA 1电流。这些效应是物种特异性的; GAs阻断啮齿动物TRPA 1而不影响果蝇直系同源物。此外，丙泊酚抑制啮齿类动物而不是人TRPA 1。嵌合TRPA 1蛋白和突变相结合的分析揭示了位于S5结构域的两个氨基酸残基，Ser 876和Thr 877，这对异氟烷和丙泊酚的抑制作用至关重要。将这些残基引入果蝇TRPA 1中可产生麻醉抑制作用。此外，几个残留物内衬的假定结合口袋有害的气体是不需要的气体的抑制作用。我们的结论是，麻醉剂抑制TRPA 1的相互作用在一个网站不同于激活网站。GAs在TRPA 1的抑制作用可能有助于这些drugs.Significance StatementWe表明，无论是有害的和非有害的全身麻醉药抑制激动剂诱发的瞬时受体电位锚蛋白1型（TRPA 1）的活动，并确定位于孔域的关键氨基酸残基的药理作用。TRPA 1的抑制可能会影响麻醉期间的疼痛和血管信号。
Several general anesthetics (GAs) produce pain or irritation upon administration, and this occurs predominantly through the activation of the nociceptive ion channel, transient receptor potential ankyrin type 1 (TRPA1). However, the effects of GAs on agonist-mediated TRPA1 activity are unclear. Here we show that a diverse range of noxious and non-noxious volatile anesthetics, at clinically relevant concentrations, inhibit ligand-activated TRPA1 currents. These effects are species-specific; GAs blocks rodent TRPA1 without affecting the Drosophila ortholog. Furthermore, propofol inhibits rodent but not human TRPA1. Analysis of chimeric TRPA1 proteins and mutagenesis combined reveals two amino acid residues located in the S5 domain, Ser876 and Thr877, that are critical for the inhibitory effects of isoflurane and propofol. Introduction of these residues into Drosophila TRPA1 confers anesthetic inhibition. Furthermore, several residues lining the presumptive binding pocket for noxious GAs are not required for the inhibitory effects of GAs. We conclude that anesthetics inhibit TRPA1 by interacting at a site distinct from the activation site. The inhibitory effects of GAs at TRPA1 may contribute to the diverse pharmacological action of these drugs.SIGNIFICANCE STATEMENTWe show that both noxious and non-noxious general anesthetics inhibit agonist-evoked transient receptor potential ankyrin type 1 (TRPA1) activity and identify critical amino acid residues located in the pore domain. Inhibition of TRPA1 may affect pain and vascular signaling during anesthesia.